Project Summary Cell death is a fundamental process in animal development and homeostasis, and misregulation of cell death is associated with a large number of human diseases. Our research program aims to understand the diverse mechanisms of cell death, how dead cells are efficiently removed, and the physiological effects on organisms when these processes go awry. We study these questions in Drosophila, a model organism with exceptional genetic, genomic and cell biological tools. The research in this proposal focuses on four key questions. The first project investigates non-apoptotic cell death, which contributes significantly to development and disease, but is poorly understood. In the Drosophila ovary, germline-derived nurse cells undergo non-apoptotic programmed cell death as part of normal development. We have found that nurse cell death is controlled largely non-autonomously by the surrounding somatic follicle cells, and current work investigates the role of lysosomes and cell signaling in this process. A second major project investigates how dead cells are removed, particularly in tissues without access to circulating phagocytes such as macrophages. In many mammalian tissues, dead cells can be cleared by epithelial cells. In a Drosophila model for engulfment by epithelial cells, starvation induces degeneration of egg chambers, where the germline is engulfed by the surrounding epithelial follicle cells. This engulfment process happens synchronously and rapidly at the onset of cell death; however the genetic requirements for engulfment by epithelial cells are not well understood. In particular, how such non-professional phagocytes can improve their phagocytic capacity is not known, and our research program will reveal the requirements for engulfment by epithelial cells. A third project addresses how phagocytic cells can promote the death of their neighbors, through a newly described type of cell death called phagoptosis. In the fourth project, we investigate the consequences of persisting cell corpses in the ovary and the brain, and how defective phagocytosis can affect disease progression. We will examine the global changes to organisms with defective cell death or phagocytosis and how defective phagocytosis interacts with genetic models of human disease. Given the high degree of conservation of cell death mechanisms between Drosophila and mammals identified thus far, we expect that pathways that we uncover in the fly will provide insight into the diversity of cell death mechanisms and consequences of defective cell removal in humans. These studies may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer.